In this laboratory the food additive (antioxidant) butylated hydroxytoluene (BHT) has been shown to inhibit the carcinogenic action of 3-hydroxyxanthine in rats by about 80 percent. This finding needs to be extended and other antioxidants tested for their suppression of carcinogenesis in the rat carcinogenesis assay. The effect of such compounds on the metabolism and intracellular distribution of 3-hydroxyxanthine will be studied. A possible effect of the carcinogen as well as the anticarcinogen on the level of cellular and urinary cyclic guanosine monophoshate will be investigated in collaboration with Dr. Ronald Coffey of this Institute. Carcinogens other than purine N-oxides are to be included in this investigation and integrated with combination assays of carcinogens and antioxidants in rat assays. 8-Methyl-3-hydroxyxanthine has proven to have a uniquely interesting mode of metabolic activation. Its sulfate ester yields an intermediate which does not react electrophilically with any of the cellular nucleophiles with which 3-hydroxyxanthine reacts. Instead it forms an oxidizing species with properties of a free radical. Its carcinogenic activity is much less than that of related strong carcinogens but it is not zero. This purine derivative will be studied as a example of a weak carcinogen with possible relevance for the action of weak environmental carcinogens. The studies will include re-assay with a larger number of rats, accompanied by further metabolic studies.